Genome-wide association study of spontaneous resolution of hepatitis C virus infection: data from multiple cohorts

Abstract

Chinese translation

Background: Hepatitis C virus (HCV) infections occur worldwide and either spontaneously resolve or persist and markedly increase the person's lifetime risk for cirrhosis and hepatocellular carcinoma. Although HCV persistence occurs more often in persons of African ancestry and persons with genetic variants near interleukin-28B (IL-28B), the genetic basis is not well-understood.

Objective: To evaluate the host genetic basis for spontaneous resolution of HCV infection.

Design: 2-stage, genome-wide association study.

Setting: 13 international multicenter study sites.

Patients: 919 persons with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 persons with serum HCV antibodies and HCV RNA (persistence).

Measurements: Frequencies of 792 721 single nucleotide polymorphisms (SNPs).

Results: Differences in allele frequencies between persons with spontaneous resolution and persistence were identified on chromosomes 19q13.13 and 6p21.32. On chromosome 19, allele frequency differences localized near IL-28B and included rs12979860 (overall per-allele OR, 0.45; P = 2.17 × 10-30) and 10 additional SNPs spanning 55 000 base pairs. On chromosome 6, allele frequency differences localized near genes for HLA class II and included rs4273729 (overall per-allele OR, 0.59; P = 1.71 × 10-16) near DQB1*03:01 and an additional 116 SNPs spanning 1 090 000 base pairs. The associations in chromosomes 19 and 6 were independent and additive and explain an estimated 14.9% (95% CI, 8.5% to 22.6%) and 15.8% (CI, 4.4% to 31.0%) of the variation in HCV resolution in persons of European and African ancestry, respectively. Replication of the chromosome 6 SNP, rs4272729, in an additional 745 persons confirmed the findings (P = 0.015).

Limitation: Epigenetic effects were not studied.

Conclusion: IL-28B and HLA class II are independently associated with spontaneous resolution of HCV infection, and SNPs marking IL-28B and DQB1*03:01 may explain approximately 15% of spontaneous resolution of HCV infection.

Figure 1

Manhattan Plot summarizing the genome-wide association results in 919 individuals with spontaneous resolution of HCV infection and 1,482 individuals with chronic HCV infection. Each point corresponds to a p-value from a test of association for a single SNP. The −log10 p values are plotted by location of the individual SNP across the genome. The dotted grey line represents an accepted level of genome wide significance, p=5 × 10⁻⁸. SNPs in the MHC and Il28b region on chromosomes 6 and 19, respectively exceed this threshold.

Figure 2. Genotyped and Imputed SNPs for HLA Class II (A) and IL28B (B) Regions

Genotyped SNPs are in dark grey, 1000 genomes imputed SNPs are in light grey. The dotted red line is p=5 × 10⁻⁸.

Figure 3. Conditional Analyses of HLA Class II and IL28B Regions

The first plot shows the genome-wide association results for HCV clearance and persistence conditioned upon rs4273729 in HLA Class II region. The second is conditioned upon rs12979860 in the IL28B region. The third plot is conditioned on both SNPs. The dotted grey line represents p= 5 × 10⁻⁸.

Figure 3. Conditional Analyses of HLA Class II and IL28B Regions

The first plot shows the genome-wide association results for HCV clearance and persistence conditioned upon rs4273729 in HLA Class II region. The second is conditioned upon rs12979860 in the IL28B region. The third plot is conditioned on both SNPs. The dotted grey line represents p= 5 × 10⁻⁸.

Figure 4. Additive Relationship for HCV clearance for HLA Class II and IL28B SNPs

Among 919 individuals with spontaneous clearance and 1482 with viral persistence, the % with viral clearance are shown for (A) rs12979860 in the IL28B region by ethnicity; (B) rs4273729 in the HLA Class II region by ethnicity; and (C) both rs4273729 and rs12979860 by ethnicity. As a case control study the relative differences in % are more informative than absolute values, which vary by the ratio of clearance to persistence in the study population.